Short-Wavelength Sensitive Cone (S-cone) Testing as an Outcome Measure for NR2E3 Clinical Treatment Trials.

Alejandro J Roman,Alexandra V Garafalo,Rebecca Sheplock,Robert C Russell,Alexander Sumaroka,Evelyn P Semenov,Samuel G Jacobson,Christian A Powers,Valeryia Aksianiuk,Artur V Cideciyan

doi:10.3390/ijms20102497

Abstract

Recessively-inherited NR2E3 gene mutations cause an unusual retinopathy with abnormally-increased short-wavelength sensitive cone (S-cone) function, in addition to reduced rod and long/middle-wavelength sensitive cone (L/M-cone) function. Progress toward clinical trials to treat patients with this otherwise incurable retinal degeneration prompted the need to determine efficacy outcome measures. Comparisons were made between three computerized perimeters available in the clinic. These perimeters could deliver short-wavelength stimuli on longer-wavelength adapting backgrounds to measure whether S-cone vision can be quantified. Results from a cohort of normal subjects were compared across the three perimeters to determine S-cone isolation and test-retest variability. S-cone perimetry data from NR2E3-ESCS (enhanced S-cone syndrome) patients were examined and determined to have five stages of disease severity. Using these stages, strategies were proposed for monitoring efficacy of either a focal or retina-wide intervention. This work sets the stage for clinical trials.

Highlights

Rare and previously incurable inherited retinal degenerations (IRDs) have recently been reconsidered as potentially treatable
Three computerized static perimeters were studied in a cohort of normal subjects using short-wavelength stimuli and longer-wavelength adapting backgrounds to determine sensitive cone (S-cone) vision across the visual field using static perimetry [6,13,23]
This isolation method takes advantage of the difference in spectral sensitivities of the S- and L/M-cone systems, which peak at different wavelengths (Figure 2A), and the differential desensitization of each produced by a high luminance yellow background [24,25]

Summary

Introduction

Rare and previously incurable inherited retinal degenerations (IRDs) have recently been reconsidered as potentially treatable. Monitoring efficacy can default to time-honored clinical measures of vision such as visual acuity [4] Such measures may be suitable outcomes for some IRDs but other disorders have retinal and visual mechanisms that are not routinely quantified. Left: Rod sensitivity (dark adapted, 500 nm); center: L/M-cone sensitivity (light adapted, 600 nm); right: S-cone (short wavelength) sensitivity (440 nm on bright yellow background), for a normal subject, and two NR2E3-ESCS patients (P17, P2). The disease expression of ESCS patients with NR2E3 gene mutations was recently reassessed, considering promising proof-of-concept murine research that could lead to clinical trials of treatment [13,14,17]. We take up the challenge to develop S-cone perimetry as an outcome measure for future clinical trials of treatment of patients with NR2E3-ESCS

Comparison of Available Computerized Perimeters for S-cone Isolation

Results Summary

Subjects

Mapping Disease Severity of NR2E3-ESCS Patients Using S-cone Perimetry